Getting High on Dopamine:
Neuroscientific Aspects of Pleasure
H. Ümit Sayin
Hedonism and pleasure are one of the main goals of human life. Pleasure can be accepted as a reward for the brain, while the major reward neurotransmitters are dopamine, norepinephrine, oxytocin and glutamate. Boost of dopamine in the “hedonic hot spots” creates euphoria, delight, pleasure, contentment and is associated with happiness. The reward circuitry and pleasure centers in the brain involve the ventral tegmental area (VTA), nucleus accumbens (NA), substantia nigra (SN), ventral pallidum, insula, lateral thalamus, cingulate cortex, hippocampus, amygdala, medial prefrontal cortex and orbitofrontal cortex. Pleasure is a learned enjoyable phenomenon and pursuing the pleasure principle is one of the crucial goals of human life. However, to some extent of pleasure, due to the release of dopamine and glutamate and the activation of D1-like excitatory dopamine receptors and NMDA receptors, may induce different forms of psychological addiction. Sexual motivation, sexual drive and orgasm also use the same reward circuitry and similar neurochemicals in the brain. The experience of “getting high on dopamine” has been one of the primary longstanding goals for human beings, as well as for other higher primates and animals during the normal course of evolution. Today, it is known that pleasure and sexual hedonism may even alter synaptic plasticity, and may influence a variety of psychological responses and the personality of individuals, as Sigmund Freud had pointed out a century ago.
KEY WORDS: pleasure center, hedonic hot spot, dopamine, glutamate, oxytocin, NMDA, reward circuit, hedonism, orgasm, motivation, sexual drive
Alex, K. D., Yavanian, G. J., McFarlane, H. G., Pluto, C. P., & Pehek, E. A.. Modulation of dopamine release by striatal 5-HT2C receptors. Synapse 2005; 55:242–251.
Amodio, D. M., & Frith, C. D. Meeting of minds: the medial frontal cortex and social cognition. Nature Reviews Neuroscience 2006; 7: 268–277.
Austin JH. Zen and the Brain. Massachusets: MIT Press, 1999.
Berke, J.D., and Hyman, S.E. Addiction, dopamine, and the molecular mechanisms of memory. Neuron 2000; 2: 515–532.
Berridge, K.C. Robinson, T.E., The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res, 1993; 18: 247–291.
Berridge KC The debate over dopamine’s role in reward: the case for incentive salience. Psychopharmacology (Berl) 2007; 191:391–431.
Berridge KC, Aldridge JW Decision utility, incentive salience, and cue-triggered ‘wanting’. In: Bargh J, Morsella E (eds) The psychology of action. Oxford University Press, New York (in press), 2008.
Berridge KC, Terry E Robinson, and J Wayne Aldridge Dissecting components of reward: ‘liking’, ‘wanting’, and learning, Curr Opin Pharmacol 2009; 9(1): 65–73.
Berridge KC, Kringelbach ML “Pleasure systems in the brain". Neuron 2015; 86 (3): 646–664.
Bjorklund A, Dunnett SB: Dopamine neuron systems in the brain: an update. Trends in Neurosciences 2007; 30(5):194-202,.
Bruinvels AT, Palacios JM, Hoyer D. Autoradiographic characterisation and localisation of 5-HT1D compared to 5-HT1B binding sites in rat brain. Naunyn Schmiedebergs Arch Pharmacol; 347: 569–582, 1993.
Carlezon, W. A., Duman, R. S., & Nestler, E. J. The many faces ofCREB. Trends Neurosci 2005; 28(8): 436–44.
Cherry K. “Freud and the Id, Ego, and Superego”. VeryWellMind.com (2018).
Craig, A. D. How do you feel—now? The anterior insula and human awareness. Nature Reviews Neuroscience 2009; 10: 59–70.
Critchley, H. D., & Rolls, E. T. Hunger and satiety modify the responses of olfactory and visual neurons in the primate orbitofrontal cortex. J Neurophysiol 1996; 75, 1673–1686.
Das S, Grunert M, Williams L, Vincent SR. NMDA and D1 receptors regulate the phosphorylation of CREB and the induction of c-fos in striatal neurons in primary culture. Synapse 1997; 25: 227–233.
Dosa PI, Ward T, Walters MA, Kim SW. Synthesis of novel analogs of cabergoline: improving cardiovascular safety by removing 5-HT2B receptor agonism. ACS Med Chem Lett 2013; 4(2): 254-258.
Franken IH, Booij J, van den Brink W. The role of dopamine in human addiction: from reward to motivated attention. Eur J Pharmacol 2005; 526: 199–206.
Funahashi S. Brain Mechanisms of Happiness, Psychologia 2011; 54: 222-233.
Freud S. “The standard edition of the complete psychological works of Sigmund Freud”. Volume XIX (1923-26) The Ego and the Id and Other Works. Strachey, James., Freud, Anna, 1895-1982, Rothgeb, Carrie Lee, 1925-, Richards, Angela, Scientific Literature Corporation.London: Hogarth Press (1978).
Freud S. “The Standard Edition of the Complete Psychological Works of Sigmund Freud”. Volume XIX. Translated from the German under the General Editorship of James Strachey. In collaboration with Anna Freud. Assisted by Alix Strachey and Alan Tyson, Vintage (1999).
Georgiadis JR, Kringelbach ML, Pfaus JG. Sex for fun: A synthesis of human and animal neurobiology. Nat Rev Urol 2012; 9: 486-498.
Hjorth S, Tao R. The putative 5-HT1B receptor agonist CP-93,129 suppresses rat hippocampal 5-HT release in vivo: comparison with RU 24969. Eur J Pharmacol 1991; 209: 249–252.
Hnasko TS, Hjelmstad GO, Fields HL, Edwards RH Ventral tegmental area glutamate neurons: electrophysiological properties and projections.J. Neurosci. 2012; 32: 15076-15085.
Hyman, S.E., and Malenka, R.C. Addiction and the brain: the neurobiology of compulsion and its persistence. Nat Rev Neurosci 2001; 2: 695–703.
Jacobs B L, Azmitia E C. Structure and function of the brain serotonin system. Physiol Rev 1992; 72:165–229.
Jannini E.A, Wise N. Frangos E. and Komisaruk BR. Peripheral and Central Neural Bases of Orgasm. In Texbook of Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition, Edited by Sue W. Goldstein, Noel N. Kim, Anita H. Clayton. New York: John Wiley & Sons Ltd, 2018. Chapter 13, pp:179-195; 2018.
Jarriault DJ, Fuller J, Hyland BI, Mercer AR. Dopamine release in mushroom bodies of honey bee (Apis mellifera L) in response to aversive stimulation. Nature, Scientific Reports 2018; 8: 16277.
Jones, B, Halaris AE, McIlhany M, Moore RY. Ascending projections of the locus coeruleus in the rat. I. Axonal transport in central noradrenalin neurons. Brain Res 1977; 127(1): 1–27.
Kandel E, Schwarz J, Jessel T. Principles of Neural Sciences, New York: Mc Graw Hill, 2013.
Kelley, A.E., and Berridge, K.C. The neuroscience of natural rewards: relevance to addictive drugs. J Neurosci 2002; 22:3306–3311.
Kim WK, Schenck CH, Grant JE, Yoon G, Dosa PI, Odlaug BL, Shreiber, LRN, Hurwitz TD, Pfaus JG. Neurobiology of Sexual Desire. SexuS Journal 2015; 1 (1): 044-076.
Komisaruk BR, Beverly Whipple. The suppression of pain by genital stimulation in females. Ann Rev Sex Res 1995; 6: 151 –186.
Komisaruk BR, Bevely W, Crawford SG, Liu WC, Kalnin A, Mosier K. Brain activation during vaginocervical self-stimulation and orgasm in women with complete spinal cord injury: fMRI evidence of mediation by vagus nerves. Brain Research 2004; 1024:77-88.
Komisaruk BR, Beverly W. Functional MRI of the brain during orgasm in women. Ann Rev Sex Res 2005; 16: 62-86.
Komisaruk BR, Whipple B. Love as a sensory stimulation: Physiological Consequences of its deprivation and expression. Psychoneuroendocrinology 1998; 8:927-944.
Komisaruk BR, Beyer-Flores C, Bevely Whipple. The Science of Orgasm, Baltimore: John Hopkins University Press, 2006.
Komisaruk BR, Sansone G. Neural pathways mediating vaginal function: The vagus nerves and spinal cord oxytocin. Scandinavian J Psychiatry 2003; 44: 241-250.
Komisaruk BR, Wise N, Frangos E, Liu WC, Allen K, Brody S. Women's clitoris, vagina, and cervix mapped on the sensory cortex: fMRI evidence, J Sex Med 2011; 8(10): 2822-30.
Konradi C, Leveque JC, and Hyman SE. Amphetamine and dopamine-induced immediate early gene expression in striatal plastic neurons depends on postsynaptic NMDA receptors and calcium. J. Neurosci 1996; 16: 4231–4239.
Koob GF, Le Moal M. Drug abuse: hedonic homeostatic dysregulation. Science 1997; 278: 52–58.
Koob GF, Volkow ND. Neurocircuitry of Addiction. Neuropsychopharmacology 2010; 35:217-238.
Koob GF, Simon EJ. The Neurobiology of Addiction: Where we have been and where are we going? J Drug Issues 2009; 39 (1) 115-132.
Koyuncuoğlu H, Dizdar Y, Arıcıoğlu F, and Sayin Ü. Effects of MK-801 on Morphine Physical Dependence: Attenuation and Intensification. Pharmacology, Biochemistry & Behavior 1992; 43: 487-490.
Koyuncuoğlu H, Sayin Ü, Dizdar Y, and Arıcıoğlu F. Effects of a Competitive NMDA Antagonist, CGP 39551, on Morphine Physical Dependence: Attenuation and Intensification. Turkish. J. Med Sci 1994; 21:163-168.
Kringelbach M L, Berridge, KC. Towards a functional neuroanatomy of pleasure and happiness. Trends in Cognitive Sciences, 2009; 13, 479–487.
Kringelbach ML, O’Doherty J, Rolls ET, & Andrews C. Activation of the human orbitofrontal cortex to a liquid food stimulus is correlated with its subjective pleasantness. Cerebral Cortex 2003; 13: 1064–1071.
LeFoll, B, Diaz J, & Sokoloff P. A single cocaine exposure increases BDNF and D3 receptor expression: implications for drug conditioning. Neuro report 2005; 16(2): 175–178.
Liste I, Guerra MJ, Caruncho, HJ, Labandeira-Garcia JL. Treadmill running induces striatal Fos expression via NMDA glutamate and dopamine receptors. Exp Brain Res 1997; 115:458–468.
Meston, CM, Frohlich PF. The Neurobiology of Sexual Function. Arch Gen Psychiatry 2000; 57: 1012-1030. Morikawa H, Manzoni OJ, Crabbe JC, Williams JT. Regulation of central synaptic transmission by 5-HT1B auto- and heteroreceptors. Mol Pharmacol 2000; 58: 1271–1278.
Ongur D, & Price JL. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cerebral Cortex 2000; 10: 206–219.
Perk CG, Mercer AR. Dopamine modulation of honey bee (Apis mellifera) Antennal-Lobe Neurons. J Neurophysiol 2006; 95: 1147-1157.
Pfaus JG, Ismail N, Coria-Avila GA. Sexual motivation. In Koob GF, Le Moal M, Thompson RF. Editors. Encyclopedia of behavioral neuroscience. Volume 3. Oxford: Academic Press, pp:201-209, 2010.
Pfaus JG, Kippin TE, Coria-Avila GA, Gelez H, AlfonsoVM, Ismail N, et al. Who, what, where, when (and maybe even why)? How the experience of sexualreward connects sexual desire, preference, and performance. Arch Sex Behav 2012; 41: 31-62.
Phillips AG, Blaha CD, & Fibiger HC. Neurochemical correlates of brain-stimulation reward measured by ex vivo and in vivo analyses. Neurosci Biobehav Rev 1989; 13: 99–104.
Robinson MJF, Fischer AM, Ahuja A, Lesser EN, . Maniates H. Roles of “Wanting” and “Liking”in Motivating Behavior: Gambling, Food and Drug Addictions. Curr Topics Behav Neurosci 2015; 2016; 27:105-36. DOI 10.1007/7854_2015_387
Rolls, E. T. The neural basis of brain-stimulation reward. Prog Neurobiol 1974; 3: 71–158.
Rolls, E. T. The orbitofrontal cortex and reward. Cerebral Cortex 2000; 10: 284–294.
Ruck CAP. Mushroom Sacraments in the Cults of Early Europe-Review. SexuS Journal 2018; 3 (7): 369-404.
Sayin Ü, Sutula TP, and Stafstrom C. Seizures in the Developing Brain Cause Adverse Long-Term Effects on Spatial Learning and Anxiety. Epilepsia 2004; 45 (12) 1539-1548.
Sayin HÜ. E Hutchinson, ME Meyerand, T Sutula. Age-dependent long-term structural and functional effects of early life seizures: evidence for a hippocampal critical period influencing plasticity in adulthood. Neuroscience Journal 2015; 288: 120-134.
Sayin HÜ, Kartal L, Yilmaz İZ, Koyuncuoglu H. The Anti-Addictive and Physiological Abstinence Blocking Effects of Ibogaine on Heroin Addiction: Via NMDA Receptors? 5th Global Ibogaine Therapy Alliance Conference, March 14-16th, Tepotzlan-Mexico 2016. In SexuS Journal 2018; 3 (9) 711-722, 2016-a. www.sexusjournal.com
Sayin HÜ, Kartal L, Yilmaz İZ. A Unified Alternative Hypothesis on the Mechanism of Action of Ibogaine, Psychoactive Plants and Entheogens. 5th Global Ibogaine Therapy Alliance Conference, March 14-16th, Tepotzlan-Mexico 2016. In SexuS Journal 2018; 3 (9) 711-722, 2016-b. www.sexusjournal.com
Sayın HÜ. A Bioelectrical Tornado in the Hippocampus: Mechanisms of Temporal Lobe Epilepsy. NeuroQuantology 2017-a; 15 (1): 92-103.
Sayin HÜ. Psychoactive Plants Consumed In Religious Rituals: Common Archetypal Symbols & Figures in Myths & Religions-Review. SexuS Journal 2017-b; 2 (5): 201-236.
Sayin HÜ. Kadın ve Orgazm: Orgazm Yöntemleri ve Yeni Cinsel Terapi Teorileri (Women and Orgasm: Orgasm Methods and Novel Sex Therapy Theories), İstanbul: Tantra Akademi/Onur Publications (480 pages), 2017-c. ISBN: 978-605-2141-02-1
Sayin HÜ. A Comparative Review of Psychopharmacology of Hallucinogen-Induced Altered States of Consciousness: Relation to Sexuality-Review. SexuS Journal 2018; 3 (7): 413-450. www.sexusjournal.com
Sayin HÜ. Cinsel Beyin (Sexual Brain-Sexual Mind). İstanbul: Tantra Akademi/Onur Publications (384 pages), 2018-b. ISBN: 978-605-2141-19-9
Sayin HÜ. Neuroanatomy and neurochemistry of sexual desire, pleasure, love and orgasm. SexuS Journal Winter 2019-a; 4:11
Sayin HÜ. The Neural Correlates of the “ID”. E-Cronicon Neurology (Review) April 4th 2019-b; 11(4): 256-273.
Schultz, W. Behavioral theories and the neurophysiology of reward. Annu. Rev. Psychol.; 57: 87–115, 2006.
Silva, A.J., Kogan, J.H., Frankland, P.W., and Kida, S. CREB and memory. Annu. Rev. Neurosci.; 21: 127–148, 1998. 284.
Spanagel, R., & Weiss, F. The dopamine hypothesis of reward: past and current status. Trends in Neuroscience, 22, 521–527, 1999.
Steffensen SC Svingos AL, Pickel VM Henriksen SJ Electrophysiological characterization of GABAergic neurons in the ventral tegmental area.J. Neurosci. 1998; 18: 8003-8015.
Steiner, H., and Kitai, S.T. Regulation of rat cortex function by D1 dopamine receptors in the striatum. J. Neurosci. 2000; 20: 5449–5460.
Steward, O., and Worley, P.F. Selective targeting of newly synthesized Arc mRNA to active synapses requires NMDA receptor activation. Neuron 2001; 30: 227–240.
Swanson, L. W., & Hartman, B. K. The central adrenergic system. An immuno-fluorescence study of the location of cell bodies and their efferent connections in the rat utilizing dopamine-beta-hydroxylase as a marker. J. Comp. Neural 1975; 163 (4): 467–505.
Terwilliger, R. Z., Beitner-Johnson, D., Sevarino, K. A., Crain, S.M., & Nestler, E. J. A general role for adaptations in G-proteinsand the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function. Brain Res 1991; 548(1–2): 100–110.
Vallone D, Picetti R, Borrelli E. Structure and function of dopamine receptors. Neurosci Biobehav Rev February 2000; 24(1): 125-32.
Volkow, N.D., Wang, G.J., Telang, F., Fowler, J.S., Logan, J., Jayne, M., Ma, Y., Pradhan, K., Wong, C. Profound decreases in dopamine release in striatum in detoxified alcoholics: possible orbitofrontal involvement. J. Neurosci 2007; 27: 12700–12706.
Wang, J.Q., Daunais, J.B., and McGinty, J.F. NMDA receptors mediate amphetamine-induced upregulation of zif/268 and prepro dynorphin mRNA expression in rat striatum. Synapse 1994; 18: 343–353.
Weidong L, Shen C, Jankovic J: Etiopathogenesis of Parkinson disease: a new beginning? Neuroscientist 2009; 15(1):28-35.
Wise NJ, Frangos E, Komisaruk BR. Brain activity Unique to Orgasm in Women: An fMRI Analysis. J Sex Med 2017; 14 (11): 1380-1391.